ABSTRACT Extensive evidence indicates that exposure to ambient particulate matter (PM) contributes to the global burden of disease. Worldwide, air pollution is linked with seven million premature deaths; and in the US, PM is associated with 200,000 deaths per year, most of which are due to cardiovascular disease (CVD). Nevertheless, the mechanisms by which PM exposure induces cardiovascular injury remain unclear. Understanding such mechanisms is important to develop mechanistically validated biomarkers of PM-induced subclinical injury and to develop effective therapeutic interventions. Mechanistic studies in individuals with mild to moderate CVD risk have implicated endothelial dysfunction and inflammation as critical mediators of PM- induced injury; however, because these mediators are also key features of CVD, it is unclear whether PM directly affects endothelial function or whether these changes are secondary to the exacerbation of CVD by PM. We found that in young, healthy individuals exposure to elevated levels of fine PM (PM2.5) suppresses circulating levels of endothelial progenitor cells (EPCs). Chronic suppression of EPCs is indicative of early endothelial injury, and, in prospective studies, predictive of CVD mortality. Nevertheless, the mechanisms by which PM2.5 suppress EPC levels remain obscure, and it is unclear whether PM2.5 affects EPC function and their ability to promote tissue repair and angiogenesis. Our preliminary data show that exposure to concentrated PM2.5 decreases the metabolic activity of EPCs and reduces their ability to repair vascular tissue. We have also found that the effects of PM2.5 are attenuated by overexpressing extracellular superoxide dismutase in the lung. Based on these observations, we propose that upon PM2.5 inhalation, pulmonary generation of superoxide impairs EPC signaling and metabolism, which compromises their ability to maintain a healthy endothelium and to promote angiogenesis. To test this hypothesis, we will determine the effects of PM2.5 exposure on EPC metabolism; assess the impact of PM2.5 exposure on EPC function; and elucidate the mechanisms by which PM2.5 exposure induces metabolic and functional changes in EPCs. Completion of this project will not only lead to a better understanding of how PM causes EPC dysfunction, but could also identify selective, specific, and mechanistically validated biomarkers of PM2.5-induced cardiovascular injury. Overall, our results would further a new concept?that PM2.5-induced cardiovascular injury is due to defective EPC metabolism?and could lead to the development of a novel approach that could be readily tested in future clinical studies to attenuate PM2.5-induced CVD mortality and morbidity.